CN100540539C - Preparation 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one - Google Patents
Preparation 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one Download PDFInfo
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- CN100540539C CN100540539C CNB2004800284205A CN200480028420A CN100540539C CN 100540539 C CN100540539 C CN 100540539C CN B2004800284205 A CNB2004800284205 A CN B2004800284205A CN 200480028420 A CN200480028420 A CN 200480028420A CN 100540539 C CN100540539 C CN 100540539C
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- methoxy ethoxy
- ethyl benzoate
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/88—Oxygen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
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Abstract
By 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate is with produced in high yields 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one.This preparation 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one are included in the carboxylic acid ammonium and exist to descend with 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate and formic acid cpds reaction.
Description
Invention field
The present invention relates to prepare 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one.
Background of invention
United States Patent (USP) 5,747,498 disclose can be as 6 of cancer therapy drug, in 7-two (2-methoxy ethoxy)-4-(3-ethynyl phenyl)-amido quinazoline hydrochloride synthetic, as 6 of intermediate, 7-two (2-methoxy ethoxy) quinazoline-4-one.
Japanese Patent temporarily openly 2002-293773 disclose and comprised 2-amino-4, the reaction of 5-two (2-methoxy ethoxy) ethyl benzoate and ammonium formiate is to make 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one.The disclosure report reaction yield is 80.5%.
Disclosure of the Invention
Problem solved by the invention
Main purpose of the present invention provides by 2-amino-4, and 5-two (2-methoxy ethoxy) ethyl benzoate is with produced in high yields 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one.
Another object of the present invention provides uses 3, and the 4-dihydric ethyl benzoate is as initial compounds, with produced in high yields 6, and the industrial advantageous method of 7-two (2-methoxy ethoxy) quinazoline-4-one.
The method of dealing with problems
At first, the invention provides preparation 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one, described method are included in the carboxylic acid ammonium and exist to descend with 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate and formic acid cpds reaction.
Secondly, the invention provides preparation 6, the method of 7-two (2-methoxy ethoxy) quinazoline-4-one, described method comprises according to following steps in order: in the presence of metal catalyst with 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction, to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate; And in the presence of the carboxylic acid ammonium with 2-amino-4, the reaction of 5-two (2-methoxy ethoxy) ethyl benzoate and formic acid cpds is to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one.
The 3rd, the invention provides preparation 6, the method of 7-two (2-methoxy ethoxy) quinazoline-4-one, described method comprises according to following steps in order: in the presence of sulfuric acid with 3,4-two (2-methoxy ethoxy) ethyl benzoate and nitric acid reaction, to make 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate; With 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction is to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate in the presence of metal catalyst; And in the presence of the carboxylic acid ammonium with 2-amino-4, the reaction of 5-two (2-methoxy ethoxy) ethyl benzoate and formic acid cpds is to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one.
The 4th, the invention provides preparation 6, the method of 7-two (2-methoxy ethoxy) quinazoline-4-one, described method comprises according to following steps in order: in the presence of alkali with 3,4-dihydric ethyl benzoate and 2-chloroethyl methyl ether react in organic solvent, to make 3,4-two (2-methoxy ethoxy) ethyl benzoate; With 3,4-two (2-methoxy ethoxy) ethyl benzoate and nitric acid reaction are to make 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate in the presence of sulfuric acid; With 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction is to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate in the presence of metal catalyst; And in the presence of the carboxylic acid ammonium with 2-amino-4, the reaction of 5-two (2-methoxy ethoxy) ethyl benzoate and formic acid cpds is to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one.
By 3, the 4-dihydric ethyl benzoate begins and generates 6, and the chemical formulation of related compound is as follows in the method for 7-two (2-methoxy ethoxy) quinazoline-4-one.
3, the 4-dihydric ethyl benzoate is represented by formula (1):
3,4-two (2-methoxy ethoxy) ethyl benzoate is represented by formula (2):
4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate is represented by formula (3):
2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate is represented by formula (4):
6,7-two (2-methoxy ethoxy) quinazoline-4-one is represented by formula (5):
Implement best mode of the present invention
By reference step in the following sequence, the present invention is described below prepares 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one:
With 3,4-dihydric ethyl benzoate and 2-chloroethyl methyl ether react in organic solvent in the presence of alkali, to make 3,4-two (2-methoxy ethoxy) ethyl benzoate (first step);
With 3,4-two (2-methoxy ethoxy) ethyl benzoate and nitric acid reaction are to make 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate (second step) in the presence of sulfuric acid;
With 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction is to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate (third step) in the presence of metal catalyst; With
With 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate and formic acid cpds reaction are to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one (the 4th step) in the presence of the carboxylic acid ammonium.
(A) first step
In first step, with 3,4-dihydric ethyl benzoate and 2-chloroethyl methyl ether react in organic solvent in the presence of alkali, to make 3,4-two (2-methoxy ethoxy) ethyl benzoate.
In first step, with the 2-chloroethyl methyl ether preferably with the 1.0-20 mole, more preferably 1.1-10 mole, most preferably the amount of 1.1-5.0 is used, by 3, the 4-dihydric ethyl benzoate is 1 mole of meter.
The example that is used for the alkali of first step comprises: alkali metal hydroxide is sodium hydroxide, potassium hydroxide for example; Alkaline carbonate is yellow soda ash and salt of wormwood for example; Alkali metal hydrocarbonate is sodium bicarbonate and saleratus for example; And alkali metal alcoholates for example sodium methylate and potassium methylate.Alkali metal hydroxide and alkaline carbonate are preferred.Alkaline carbonate is preferred.Salt of wormwood is most preferred.Alkali can be used alone or in combination.
With alkali preferably with the 1.0-20 mole, more preferably 1.1-10 mole, most preferably the amount of 1.1-5.0 mole is used, by 3, the 4-dihydric ethyl benzoate is 1 mole of meter.
Remove non-solvent and participate in reaction, otherwise be not particularly limited for the organic solvent that is used for first step.The example of organic solvent comprises: alcohol is methyl alcohol, ethanol, Virahol and the trimethyl carbinol for example; Ketone is acetone, methylethylketone and methyl iso-butyl ketone (MIBK) for example; Acid amides is N for example, dinethylformamide and N-Methyl pyrrolidone; Ureas is N for example, N '-methylimidazole alkane ketone; Sulfoxide is methyl-sulphoxide for example; Nitrile is acetonitrile and propionitrile for example; Ether is ether, diisopropyl ether, tetrahydrofuran (THF) He diox for example; And aromatic hydrocarbons for example toluene and dimethylbenzene.Ketone, nitrile and acid amides are preferred.Organic solvent can be used alone or in combination.
The amount that can regulate organic solvent according to the homogeneity and the agitation condition of reaction soln.Organic solvent is preferably with 1-100g, and more preferably the amount of 2-20g is used, and by 3, the 4-dihydric ethyl benzoate is the 1g meter.
For example, can pass through 3,4-dihydric ethyl benzoate, 2-chloroethyl methyl ether, alkali and organic solvent mix under inert atmosphere, carry out first step.Temperature of reaction is preferably 20-200 ℃, more preferably 40-120 ℃.Be not particularly limited for reaction pressure.
In first step, obtain 3,4-two (2-methoxy ethoxy) ethyl benzoate.After reaction is finished, can be with 3,4-two (2-methoxy ethoxy) ethyl benzoate isolated or purified is to be used for second step.Can for example filter according to ordinary method, concentrate, distillation, recrystallization, crystallization or column chromatography carry out isolated or purified.Also can be with 3,4-two (2-methoxy ethoxy) ethyl benzoate is used for second step without isolated or purified.Do not carrying out under the situation of isolated or purified, can be with solvent exchange in second step.
(B) second step
In second step, with 3,4-two (2-methoxy ethoxy) ethyl benzoate and nitric acid reaction are to make 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate in the presence of sulfuric acid.
In second step, nitric acid is preferably with the 1.0-50 mole, and more preferably the amount of 2.0-10 mole is used, and by 3,4-two (2-methoxy ethoxy) ethyl benzoate is 1 mole of meter.The concentration of nitric acid is preferably 40-90wt.%, more preferably 50-70wt.%.
Second step is preferably carried out in the presence of solvent.Remove non-solvent and participate in reaction, otherwise have no particular limits for solvent.The example of solvent comprises carboxylic acid for example formic acid, acetate, propionic acid and butyric acid.Acetate is preferred.Solvent can separately and be used in combination.
The amount that can regulate solvent according to the homogeneity and the agitation condition of reaction soln.Solvent is preferably with 1-50g, and more preferably the amount of 1.1-20g is used, and by 3,4-two (2-methoxy ethoxy) ethyl benzoate is the 1g meter.
For example, can pass through 3,4-two (2-methoxy ethoxy) ethyl benzoate, nitric acid, sulfuric acid and solvent mix under inert atmosphere, carry out second step.Temperature of reaction is preferably 20-90 ℃, more preferably 30-80 ℃, most preferably is 45-75 ℃.Be not particularly limited for reaction pressure.
In second step, obtain 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate.After reaction is finished, can be with 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate isolated or purified is to be used for third step.Can for example filter according to ordinary method, concentrate, distillation, recrystallization, crystallization or column chromatography carry out isolated or purified.Also can be with 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate is purified and be used for third step.Do not carrying out under the situation of isolated or purified, can be with solvent exchange in third step.
(C) third step
In third step, with 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction is to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate in the presence of metal catalyst.
The metal catalyst that is used for third step can contain at least a atoms metal that is selected from palladium, platinum and nickel.The example of metal catalyst comprises palladium/carbon, palladium/barium sulfate, palladium hydroxide/carbon, platinum/carbon, platinum sulfide/carbon, palladium-platinum/carbon, platinum oxide and Raney nickel.Palladium/carbon, platinum/carbon, platinum sulfide/carbon and Raney nickel are preferred.Platinum/C catalyst is particularly preferred.Metal catalyst can be used alone or in combination.
In third step, metal catalyst is preferably with 0.1-1, and 000mg more preferably uses with the amount of 0.5-500mg, and described amount is in the amount of atoms metal, and by 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate is the 1g meter.When metal catalyst comprised the metal that is carried on the carrier, the amount of the metal on the carrier was preferably the 1-2.9wt.% of vehicle weight.
In third step, hydrogen is preferably with the 3-50 mole, and more preferably the amount of 3-10 mole is used, and by 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate is 1 mole of meter.
Reaction in the third step is preferably carried out in the presence of solvent.Remove non-solvent and participate in reaction, otherwise have no particular limits for solvent.The example of solvent comprises: water; Alcohol is methyl alcohol, ethanol, Virahol, n-propyl alcohol and the trimethyl carbinol for example; Carboxylicesters is methyl acetate, ethyl acetate and methyl propionate for example; Aromatic hydrocarbons is benzene,toluene,xylene and 1 for example; Ether is ether, tetrahydrofuran (THF) He diox for example.The alcohol and carboxylic acid ester is preferred, and methyl alcohol and ethanol are preferred.Solvent can be used alone or in combination.
The amount that can regulate solvent according to the homogeneity and the agitation condition of reaction soln.Solvent is preferably with 1-100g, and more preferably the amount of 2-30g is used, and by 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate is the 1g meter.
For example, can be by with 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate, metal catalyst and solvent mix in the presence of hydrogen (can with the hydrogen inert gas dilution), carry out third step.Temperature of reaction is preferably 0-300 ℃, more preferably 20-200 ℃.Reaction pressure is preferably 0.1-10Mpa, more preferably 0.1-2Mpa.
After reaction is finished, can be with end product, i.e. 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate isolated or purified is to be used for the 4th step.Can for example filter according to ordinary method, concentrate, distillation, recrystallization, crystallization or column chromatography carry out isolated or purified.Also can be with 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate is used for the 4th step without isolated or purified.Do not carrying out under the situation of isolated or purified, can be with solvent exchange in the 4th step.
(D) the 4th step
In the 4th step, with 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate and formic acid cpds reaction are to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one in the presence of the carboxylic acid ammonium.
The example of formic acid cpds comprises: formic acid; Manthanoate is formic acid and the ester (for example methyl-formiate and ethyl formate) with lower alcohol of 1-6 carbon atom for example; With ortho-formiate for example orthoformic acid with have the ester (for example original acid A ester and ethyl orthoformate) of the lower alcohol of 1-6 carbon atom.Manthanoate and ortho-formiate are preferred.Ortho-formiate is preferred.Original acid A ester and ethyl orthoformate are most preferred.
In the 4th step, formic acid cpds is preferably with the 1.0-30 mole, and more preferably the amount of 1.1-10 mole is used, and presses 2-amino-4, and 5-two (2-methoxy ethoxy) ethyl benzoate is 1 mole of meter.
In the 4th step, use the carboxylic acid ammonium.Carboxylic acid ammonium's example comprises: the aliphatic carboxylic acid ammonium for example has the aliphatic acid acid ammonium (for example ammonium formiate, ammonium acetate and propionic acid ammonium) of 1-6 carbon atom; For example has aromatic carboxylic acid's ammonium (for example ammonium benzoate and dichlorobenzoic acid ammonium) of 7-12 carbon atom with aromatic carboxylic acid's ammonium.The aliphatic carboxylic acid ammonium is preferred.Ammonium formiate and ammonium acetate are preferred.Ammonium acetate is most preferred.The carboxylic acid ammonium can be used alone or in combination.
In the 4th step, the carboxylic acid ammonium is preferably with the 1.0-30 mole, and more preferably the amount of 1.1-10 mole is used, and presses 2-amino-4, and 5-two (2-methoxy ethoxy) ethyl benzoate is 1 mole of meter.
In the 4th step, reaction can be carried out in the presence of solvent.Reaction also can be carried out under the situation of solvent not having.Remove non-solvent and participate in reaction, otherwise have no particular limits for solvent.The example of solvent comprises alcohol for example methyl alcohol, ethanol, Virahol, propyl carbinol and the trimethyl carbinol; Acid amides is N for example, dinethylformamide and N-Methyl pyrrolidone; Ureas is N for example, N '-methylimidazole alkane ketone; Sulfoxide is methyl-sulphoxide for example; Aromatic hydrocarbons is benzene,toluene,xylene and 1 for example; Halohydrocarbon is methylene dichloride, chloroform and ethylene dichloride for example; Nitrile is acetonitrile and propionitrile for example; And ether for example ether, tetrahydrofuran (THF) He diox.Alcohol, acid amides and nitrile are preferred.Methyl alcohol, ethanol, N, N '-methylimidazole alkane ketone and acetonitrile are preferred.Solvent can be used alone or in combination.
The amount that can regulate solvent according to the homogeneity and the agitation condition of reaction soln.Solvent is preferably with 0-50g, more preferably 0-20g, and most preferably the amount of 0-5g is used, and press 2-amino-4, and 5-two (2-methoxy ethoxy) ethyl benzoate is that 1g counts.
For example, can pass through carboxylic acid ammonium, 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate, formic acid cpds and solvent mix under inert atmosphere, carry out the reaction of the 4th step.Temperature of reaction is preferably 40-200 ℃, more preferably 50-150 ℃.Be not particularly limited for reaction pressure.
After reaction is finished, can be with end product, promptly 6,7-two (2-methoxy ethoxy) quinazoline-4-one carries out isolated or purified.Can for example filter according to ordinary method, concentrate, distillation, recrystallization, crystallization or column chromatography carry out isolated or purified.
Come the present invention is further described by the following examples.
Embodiment
[synthetic embodiment 1]
(synthesizing 3,4-two (2-methoxy ethoxy) ethyl benzoate)
In the glass reactor of outfit with the 20L volume of agitator, thermometer and reflux exchanger, put into 1,300g (7.14 moles) 3,4-dihydric ethyl benzoate, 2,324g (21.4 moles) 2-chloroethyl methyl ether, 2,958g (21.4 moles) salt of wormwood and 6,500mL N, dinethylformamide.Under 90-100 ℃ of stirring, make mixture react to each other 9 hours.After reacting completely, reaction soln is cooled to room temperature.Then reaction soln is filtered, and with 6, the 500mL washing with acetone.Filtrate is concentrated, in enriched material, add 3,900mL ethyl acetate and 3,900mL saturated aqueous sodium carbonate.With 3,900mL saturated sodium-chloride water solution washed twice obtains to contain 3, the solution mixture of 4-two (2-methoxy ethoxy) ethyl benzoate with isolating organic layer (ethyl acetate layer).With solution mixture high-efficient liquid phase chromatogram technique analysis (according to the absolute quantitation method).Confirmation has generated 2, and 023g 3,4-two (2-methoxy ethoxy) ethyl benzoate (reaction yield: 95%).In solution mixture, add 3, behind the 939mL acetate, the mixture concentrating under reduced pressure is removed ethyl acetate with distillation.Like this, obtain 3, the acetic acid solution of 4-two (2-methoxy ethoxy) ethyl benzoate.
[synthetic embodiment 2]
(synthesizing 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate)
In the glass reactor of outfit, put into and contain 2,3 of synthetic embodiment 1 preparation of 023g (6.78 moles), the acetic acid solution of 4-two (2-methoxy ethoxy) ethyl benzoate with the 20L volume of agitator, thermometer and reflux exchanger.318g (3.18 moles) vitriol oil is added in this solution under stirring at room lightly.This mixture heating up to 60-70 ℃.With 1,857g (20.34 moles) 69wt.% nitric acid stirs down and is added to lightly in this mixture.When keeping temperature, made the gained mixture reaction 2 hours.After reacting completely, temperature of reaction is cooled to room temperature.With 5, the 20wt.% sodium chloride aqueous solution and 5 of 200mL, 200mL toluene is added in the reaction soln.With 7, the aqueous sodium hydroxide washes of the 1 mole/L of 800mL washs twice, and further uses 7 with isolating organic layer (toluene layer), the 20wt.% sodium chloride aqueous solution washed twice of 800mL.The organic layer concentrating under reduced pressure, obtain 2,328g 4, and 5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate is orange liquid (isolated yield: 100%).
[synthetic embodiment 3]
(Synthetic 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate)
In the glass reactor of outfit with the 20L volume of agitator, thermometer and reflux exchanger, put into 2,4 of synthetic embodiment 2 preparations of 328g (6.78 moles), 5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate, 2wt.% platinum/118g carbon (50wt.% product, N.E.Chemcat Corporation, in 6.0 moles in platinum atom) and 9,440mL methyl alcohol.Make mixture under nitrogen atmosphere in 50-60 ℃ of stirring reaction 6 hours.After reacting completely, reaction soln is cooled to room temperature, and filters.Filtrate decompression is concentrated, obtain 1,960g 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate is orange liquid (isolated yield: 92%).
[synthetic embodiment 4]
(synthesizing 6,7-two (2-methoxy ethoxy) quinazoline-4-one)
In the glass reactor of outfit with the 20L volume of agitator, thermometer and reflux exchanger, put into 1, the 2-amino-4 of synthetic embodiment 3 preparations of 600g (5.11 moles), 5-two (2-methoxy ethoxy) ethyl benzoate, 1,626g (15.3 moles) original acid A ester, 1,181g (15.3 moles) ammonium acetate and 4,800mL methyl alcohol.Make mixture descend stirring reaction 7 hours at reflux conditions (60-70 ℃).After reacting completely, reaction soln is cooled to 60 ℃.In reaction soln, add 4,800mL methyl alcohol.When keeping temperature, mixture was stirred 30 minutes, be cooled to 5 ℃, and further stirred 1 hour.Filter the gained mixture, obtain 1,373g 6, and 7-two (2-methoxy ethoxy) quinazoline-4-one is white crystal (isolated yield: 91%).
Based on 3, the overall yield of 4-dihydric ethyl benzoate is 80%.
Claims (6)
1. prepare 6, the method for 7-two (2-methoxy ethoxy) quinazoline-4-one, described method comprise that with 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate and ortho-formiate react in the presence of ammonium acetate.
2. prepare 6, the method of 7-two (2-methoxy ethoxy) quinazoline-4-one, described method comprises according to following steps in order: in the presence of metal catalyst with 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction, to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate; And in the presence of ammonium acetate with 2-amino-4, the reaction of 5-two (2-methoxy ethoxy) ethyl benzoate and ortho-formiate is to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one.
3. prepare 6, the method of 7-two (2-methoxy ethoxy) quinazoline-4-one, described method comprises according to following steps in order: in the presence of sulfuric acid with 3,4-two (2-methoxy ethoxy) ethyl benzoate and nitric acid reaction, to make 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate; With 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction is to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate in the presence of metal catalyst; And in the presence of ammonium acetate with 2-amino-4, the reaction of 5-two (2-methoxy ethoxy) ethyl benzoate and ortho-formiate is to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one.
4. prepare 6, the method of 7-two (2-methoxy ethoxy) quinazoline-4-one, described method comprises according to following steps in order: in the presence of alkali with 3,4-dihydric ethyl benzoate and 2-chloroethyl methyl ether react in organic solvent, to make 3,4-two (2-methoxy ethoxy) ethyl benzoate; With 3,4-two (2-methoxy ethoxy) ethyl benzoate and nitric acid reaction are to make 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate in the presence of sulfuric acid; With 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate and H-H reaction is to make 2-amino-4,5-two (2-methoxy ethoxy) ethyl benzoate in the presence of metal catalyst; And in the presence of ammonium acetate with 2-amino-4, the reaction of 5-two (2-methoxy ethoxy) ethyl benzoate and ortho-formiate is to make 6,7-two (2-methoxy ethoxy) quinazoline-4-one.
5. claim 3 or 4 method, wherein in the presence of sulfuric acid 3, the reaction of 4-two (2-methoxy ethoxy) ethyl benzoate and nitric acid is to carry out under 45-75 ℃ temperature, to make 4,5-two (2-methoxy ethoxy)-2-ethyl nitrobenzoate.
6. claim 3 or 4 method, wherein said metal catalyst comprises the platinum that is carried on the 1-2.9wt% on the carbon support.
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| AT (1) | ATE503747T1 (en) |
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| CN106928069A (en) * | 2017-03-21 | 2017-07-07 | 上海玉函化工有限公司 | A kind of preparation method of 4,5 2 (2 methoxy ethoxy) 2 ethyl nitrobenzoates |
| CN108358798A (en) * | 2018-02-12 | 2018-08-03 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Tarceva intermediate |
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|---|---|---|---|---|
| WO2003064399A1 (en) * | 2002-01-28 | 2003-08-07 | Ube Industries, Ltd. | Process for producing quinazolin-4-one derivative |
| JP5236293B2 (en) | 2005-01-13 | 2013-07-17 | ブリストル−マイヤーズ スクイブ カンパニー | Substituted biaryl compounds as XIA factor inhibitors |
| CN101798289B (en) * | 2010-02-08 | 2012-04-18 | 天津市炜杰科技有限公司 | Preparation method of erlotinib intermediate |
| CN102321033B (en) * | 2011-08-22 | 2013-10-09 | 江苏辉丰农化股份有限公司 | Preparation method of tarceva |
| WO2013156835A1 (en) * | 2012-04-16 | 2013-10-24 | Laurus Labs Private Limited | An improved process for the preparation of erlotinib hydrochloride form a |
| CN102850279A (en) * | 2012-10-10 | 2013-01-02 | 山东金城医药化工股份有限公司 | Preparation method of 6, 7-bi (2-methoxyl ethyoxyl) quinazoline-4-ketone |
| CN104725327B (en) * | 2015-03-03 | 2017-08-25 | 山东大学 | A kind of environment-friendly preparation method of erlotinib Hydrochloride |
| CN106892821B (en) * | 2015-12-21 | 2021-06-11 | 浙江九洲药业股份有限公司 | Preparation method of 3, 4-di (2-methoxyethoxy) ethyl benzoate |
| CN105566233B (en) * | 2015-12-31 | 2018-08-17 | 重庆威鹏药业有限公司 | The preparation method of Tarceva intermediate |
| CN113603650B (en) * | 2021-08-03 | 2023-03-10 | 杭州职业技术学院 | Catalytic cyclization preparation method and application of erlotinib key intermediate |
Family Cites Families (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3119824A (en) * | 1964-01-28 | L-substituted-l | ||
| US4096144A (en) * | 1970-12-08 | 1978-06-20 | Sumitomo Chemical Company, Limited | Process for preparing quinazolinone derivatives and their 2-(N-mono-substituted amino)-phenyl ketone intermediate derivatives |
| JPS63126867A (en) * | 1986-11-14 | 1988-05-30 | Mitsui Petrochem Ind Ltd | Production of imidazole derivative |
| JPH0629234B2 (en) * | 1986-12-26 | 1994-04-20 | 三井石油化学工業株式会社 | α-acyloxyketone derivative |
| PT100905A (en) * | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | BICYCLE HYGIENEOUS HETEROCYCLIC COMPOUNDS CONTAINING BENZENE, CYCLOHEXAN OR PYRIDINE AND PYRIMIDINE, PYRIDINE OR IMIDAZOLE SUBSTITUTES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
| EP1309567A2 (en) * | 2000-08-18 | 2003-05-14 | Millennium Pharmaceuticals, Inc. | Nitrogenous heterocyclic compounds |
| JP2002293773A (en) * | 2001-03-30 | 2002-10-09 | Sumika Fine Chemicals Co Ltd | Method for producing quinazoline derivative |
| US7132427B2 (en) | 2001-06-21 | 2006-11-07 | Ariad Pharmaceuticals, Inc. | Quinazolines and uses thereof |
| US7232903B2 (en) * | 2001-12-19 | 2007-06-19 | Ube Industries, Ltd. | Process for producing quinazolin-4-one and derivatives thereof |
| WO2003064399A1 (en) * | 2002-01-28 | 2003-08-07 | Ube Industries, Ltd. | Process for producing quinazolin-4-one derivative |
| DE10204150A1 (en) | 2002-02-01 | 2003-08-14 | Schott Glas | Alkaline earth aluminosilicate glass and use |
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2004
- 2004-07-30 JP JP2005512534A patent/JP4569876B2/en not_active Expired - Fee Related
- 2004-07-30 CN CNB2004800284205A patent/CN100540539C/en not_active Expired - Fee Related
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- 2004-07-30 DE DE602004032028T patent/DE602004032028D1/en not_active Expired - Lifetime
- 2004-07-30 ES ES04748126T patent/ES2362734T3/en not_active Expired - Lifetime
- 2004-07-30 WO PCT/JP2004/010965 patent/WO2005012264A1/en active Application Filing
- 2004-07-30 EP EP04748126A patent/EP1650196B1/en not_active Expired - Lifetime
- 2004-07-30 US US10/565,981 patent/US20060276647A1/en not_active Abandoned
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106928069A (en) * | 2017-03-21 | 2017-07-07 | 上海玉函化工有限公司 | A kind of preparation method of 4,5 2 (2 methoxy ethoxy) 2 ethyl nitrobenzoates |
| CN108358798A (en) * | 2018-02-12 | 2018-08-03 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Tarceva intermediate |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1860105A (en) | 2006-11-08 |
| US8133999B2 (en) | 2012-03-13 |
| JPWO2005012264A1 (en) | 2007-09-27 |
| US20060276647A1 (en) | 2006-12-07 |
| ATE503747T1 (en) | 2011-04-15 |
| DE602004032028D1 (en) | 2011-05-12 |
| WO2005012264A1 (en) | 2005-02-10 |
| EP1650196B1 (en) | 2011-03-30 |
| EP1650196A1 (en) | 2006-04-26 |
| EP1650196A4 (en) | 2007-02-28 |
| US20090253909A1 (en) | 2009-10-08 |
| ES2362734T3 (en) | 2011-07-12 |
| JP4569876B2 (en) | 2010-10-27 |
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